Showing papers by "University of Iceland published in 2014"
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
6,809 citations
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
1,872 citations
Dalhousie University1, University of Alabama at Birmingham2, Mount Sinai Hospital3, University of Göttingen4, Manchester Academic Health Science Centre5, Hospital de Sant Pau6, Jikei University School of Medicine7, University of Iceland8, National Taiwan University9, University of Texas Health Science Center at San Antonio10, Novartis11
TL;DR: Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target and the rates of infection were higher with secuk inumab than with placebo in both studies and were similar to those with etanercept.
Abstract: BACKGROUND: Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (coprimary end points). RESULTS: The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigator's global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS: Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).
1,587 citations
Valentina Escott-Price1, Céline Bellenguez2, Li-San Wang3, Seung Hoan Choi4 +191 more•Institutions (67)
TL;DR: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimers disease.
Abstract: Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This s ...
1,518 citations
TL;DR: In this paper, the authors aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry.
Abstract: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
954 citations
TL;DR: Experimental results demonstrate that the proposed edge-preserving filtering based classification method can improve the classification accuracy significantly in a very short time and can be easily applied in real applications.
Abstract: The integration of spatial context in the classification of hyperspectral images is known to be an effective way in improving classification accuracy. In this paper, a novel spectral-spatial classification framework based on edge-preserving filtering is proposed. The proposed framework consists of the following three steps. First, the hyperspectral image is classified using a pixelwise classifier, e.g., the support vector machine classifier. Then, the resulting classification map is represented as multiple probability maps, and edge-preserving filtering is conducted on each probability map, with the first principal component or the first three principal components of the hyperspectral image serving as the gray or color guidance image. Finally, according to the filtered probability maps, the class of each pixel is selected based on the maximum probability. Experimental results demonstrate that the proposed edge-preserving filtering based classification method can improve the classification accuracy significantly in a very short time. Thus, it can be easily applied in real applications.
640 citations
TL;DR: It is shown in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45), and various tests of cognitive function are used to demonstrate that control subjects carrying theCNVs perform at a level that is between that of schizophrenia patients and population controls.
Abstract: In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.
617 citations
TL;DR: In this paper, the authors focus on the challenging problem of hyperspectral image classification, which has recently gained in popularity and attracted the interest of other scientific disciplines such as machine learning, image processing, and computer vision.
Abstract: The technological evolution of optical sensors over the last few decades has provided remote sensing analysts with rich spatial, spectral, and temporal information. In particular, the increase in spectral resolution of hyperspectral images (HSIs) and infrared sounders opens the doors to new application domains and poses new methodological challenges in data analysis. HSIs allow the characterization of objects of interest (e.g., land-cover classes) with unprecedented accuracy, and keeps inventories up to date. Improvements in spectral resolution have called for advances in signal processing and exploitation algorithms. This article focuses on the challenging problem of hyperspectral image classification, which has recently gained in popularity and attracted the interest of other scientific disciplines such as machine learning, image processing, and computer vision. In the remote sensing community, the term classification is used to denote the process that assigns single pixels to a set of classes, while the term segmentation is used for methods aggregating pixels into objects and then assigned to a class.
599 citations
TL;DR: Gross domestic product (GDP) is a misleading measure of national success as discussed by the authors, and countries should act now to embrace new metrics, urge Robert Costanza and colleagues, and they do not.
Abstract: Gross domestic product is a misleading measure of national success. Countries should act now to embrace new metrics, urge Robert Costanza and colleagues.
498 citations
TL;DR: In this article, the authors used genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies and found robust evidence for 123 signals at 106 genomic loci associated with age at menarche.
Abstract: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
498 citations
TL;DR: Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner, lending support to the inflammation hypothesis in vascular disease.
Abstract: Aims Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies.
Methods and results Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21–1.54) for IL-6, 1.26 (1.11–1.44) for IL-18, 1.30 (1.16–1.46) for MMP-9, 1.01 (0.89–1.15) for sCD40L, and 1.13 (1.01–1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08–1.46) for IL-6, 1.12 (0.95–1.31) for IL-18, 1.21 (1.05–1.39) for MMP-9, 0.93 (0.78–1.11) for sCD40L, and 1.14 (1.00–1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19–1.32) for IL-6; 1.13 (1.05–1.20) for IL-18; 1.07 (0.97–1.19) for MMP-9; 1.07 (0.95–1.21) for sCD40L; and 1.17 (1.09–1.25) for TNF-α.
Conclusions Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.
Broad Institute1, Harvard University2, deCODE genetics3, University of Oxford4, University of Copenhagen5, University of Michigan6, Yeshiva University7, Texas Biomedical Research Institute8, Wake Forest University9, University of Southern Denmark10, Pfizer11, Ealing Hospital12, National Health Service13, Imperial College London14, Hallym University15, Lund University16, University of Helsinki17, University of Texas Health Science Center at Houston18, Norwegian University of Science and Technology19, Uppsala University20, University of Bergen21, Aalborg University22, Novo Nordisk23, University of Eastern Finland24, Technische Universität München25, University of North Carolina at Chapel Hill26, University of Liverpool27, National Institute for Health and Welfare28, National University of Singapore29, Agency for Science, Technology and Research30, University of Iceland31, King Abdulaziz University32, Danube University Krems33, University of Pennsylvania34, University of Mississippi35, Churchill Hospital36, Massachusetts Institute of Technology37
TL;DR: In this article, the authors identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels.
Abstract: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
Wellcome Trust Sanger Institute1, University of Santiago de Compostela2, University College London3, Haukeland University Hospital4, University of Bergen5, Katholieke Universiteit Leuven6, University of Cambridge7, University of Liverpool8, University of East Anglia9, Institute of Cancer Research10, University of Tampere11, Johns Hopkins University12, Netherlands Cancer Institute13, Université libre de Bruxelles14, Erasmus University Medical Center15, University of Iceland16, University of Queensland17, Royal Brisbane and Women's Hospital18, University of Lyon19, Oslo University Hospital20, Radboud University Nijmegen21, Harvard University22, Curie Institute23, Royal National Orthopaedic Hospital24, University of Texas MD Anderson Cancer Center25
TL;DR: It is found that 3′ transduction activity in a patient’s tumor was always associated with hypomethylation of that element, and in some cases transduction events can scatter exons, genes, and regulatory elements widely across the genome.
Abstract: Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.
TL;DR: In this article, the authors analyzed 50 months of Fermi Large Area Telescope (LAT) data between 100 MeV and 500 GeV above 10 deg in Galactic latitude to derive the spectrum and morphology of two large structures in the gamma-ray sky extending to 55 deg below the Galactic center.
Abstract: The Fermi bubbles are two large structures in the gamma-ray sky extending to 55 deg above and below the Galactic center. We analyze 50 months of Fermi Large Area Telescope data between 100 MeV and 500 GeV above 10 deg in Galactic latitude to derive the spectrum and morphology of the Fermi bubbles. We thoroughly explore the systematic uncertainties that arise when modeling the Galactic diffuse emission through two separate approaches. The gamma-ray spectrum is well described by either a log parabola or a power law with an exponential cutoff. We exclude a simple power law with more than 7 sigma significance. The power law with an exponential cutoff has an index of 1.90+/-0.2 and a cutoff energy of 110+/- 50 GeV. We find that the gamma-ray luminosity of the bubbles is 4.4(+)2.4(-0.9 ) 10(exp 37) erg s-1. We confirm a significant enhancement of gamma-ray emission in the south-eastern part of the bubbles, but we do not find significant evidence for a jet. No significant variation of the spectrum across the bubbles is detected. The width of the boundary of the bubbles is estimated to be 3.4(+)3.7(-)2.6 deg. Both inverse Compton (IC) models and hadronic models including IC emission from secondary leptons t the gamma-ray data well. In the IC scenario, the synchrotron emission from the same population of electrons can also explain the WMAP and Planck microwave haze with a magnetic field between 5 and 20 micro-G.
Ludwig Maximilian University of Munich1, University of Lübeck2, Harvard University3, deCODE genetics4, University of Maryland, Baltimore5, Stanford University6, University of Newcastle7, National Institutes of Health8, Boston University9, University of Washington10, Synlab Group11, Mayo Clinic12, Erasmus University Rotterdam13, University of Ottawa14, University of Iceland15, Broad Institute16, University of Edinburgh17, University of Pennsylvania18, Imperial College London19, Clinical Trial Service Unit20, Wellcome Trust Centre for Human Genetics21, University of Oxford22, Technische Universität München23, St George's, University of London24, University of Leicester25
TL;DR: In this article, the authors conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases and found substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
Abstract: BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)). CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
Broad Institute1, University of Wisconsin–Milwaukee2, University of Washington3, University of Texas Health Science Center at Houston4, Washington University in St. Louis5, University of Pennsylvania6, Erasmus University Rotterdam7, University of Edinburgh8, University of Virginia9, Wake Forest University10, University of Iceland11, Boston University12, Fred Hutchinson Cancer Research Center13, Ohio State University14, University of Iowa15, University of Pittsburgh16, University of Minnesota17, National Institutes of Health18, University of California, Los Angeles19, Yale University20, Icahn School of Medicine at Mount Sinai21, Lund University22, University of Milan23, University of Oxford24, University of Verona25, Duke University26, University of Ottawa27, Merck & Co.28, University of Mississippi29, University of North Carolina at Chapel Hill30, University of Split31, Tufts University32, Harvard University33, Baylor College of Medicine34
TL;DR: Although the "Exome Array" was used to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals, none of these four variants was associated with risk for CHD, suggesting that examples of low- frequencies with robust effects on both lipids and CHD will be limited.
Abstract: Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
TL;DR: Considering that regions of different scales incorporate the complementary yet correlated information for classification, a multiscale adaptive sparse representation (MASR) model is proposed and demonstrates the qualitative and quantitative superiority of the proposed MASR algorithm when compared to several well-known classifiers.
Abstract: Sparse representation has been demonstrated to be a powerful tool in classification of hyperspectral images (HSIs). The spatial context of an HSI can be exploited by first defining a local region for each test pixel and then jointly representing pixels within each region by a set of common training atoms (samples). However, the selection of the optimal region scale (size) for different HSIs with different types of structures is a nontrivial task. In this paper, considering that regions of different scales incorporate the complementary yet correlated information for classification, a multiscale adaptive sparse representation (MASR) model is proposed. The MASR effectively exploits spatial information at multiple scales via an adaptive sparse strategy. The adaptive sparse strategy not only restricts pixels from different scales to be represented by training atoms from a particular class but also allows the selected atoms for these pixels to be varied, thus providing an improved representation. Experiments on several real HSI data sets demonstrate the qualitative and quantitative superiority of the proposed MASR algorithm when compared to several well-known classifiers.
TL;DR: Temporal and spectral analyses of GRB 130427A challenge the widely accepted model that the nonthermal high-energy emission in the afterglow phase of GRBs is synchrotron emission radiated by electrons accelerated at an external shock.
Abstract: The observations of the exceptionally bright gamma-ray burst (GRB) 130427A by the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope provide constraints on the nature of these unique astrophysical sources. GRB 130427A had the largest fluence, highest-energy photon (95 GeV), longest gamma-ray duration (20 hours), and one of the largest isotropic energy releases ever observed from a GRB. Temporal and spectral analyses of GRB 130427A challenge the widely accepted model that the nonthermal high-energy emission in the afterglow phase of GRBs is synchrotron emission radiated by electrons accelerated at an external shock.
TL;DR: The computational effort in finding the minimum energy path with DFT was reduced by a factor ranging from 50% to an order of magnitude by using an IDPP path as the initial path.
Abstract: A method is presented for generating a good initial guess of a transition path between given initial and final states of a system without evaluation of the energy. An objective function surface is constructed using an interpolation of pairwise distances at each discretization point along the path and the nudged elastic band method then used to find an optimal path on this image dependent pair potential (IDPP) surface. This provides an initial path for the more computationally intensive calculations of a minimum energy path on an energy surface obtained, for example, by ab initio or density functional theory. The optimal path on the IDPP surface is significantly closer to a minimum energy path than a linear interpolation of the Cartesian coordinates and, therefore, reduces the number of iterations needed to reach convergence and averts divergence in the electronic structure calculations when atoms are brought too close to each other in the initial path. The method is illustrated with three examples: (1) rotation of a methyl group in an ethane molecule, (2) an exchange of atoms in an island on a crystal surface, and (3) an exchange of two Si-atoms in amorphous silicon. In all three cases, the computational effort in finding the minimum energy path with DFT was reduced by a factor ranging from 50% to an order of magnitude by using an IDPP path as the initial path. The time required for parallel computations was reduced even more because of load imbalance when linear interpolation of Cartesian coordinates was used.
TL;DR: In this paper, the authors identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization.
Abstract: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
TL;DR: Compared with other hyperspectral classification methods, the proposed IFRF method shows outstanding performance in terms of classification accuracy and computational efficiency.
Abstract: Feature extraction is known to be an effective way in both reducing computational complexity and increasing accuracy of hyperspectral image classification. In this paper, a simple yet quite powerful feature extraction method based on image fusion and recursive filtering (IFRF) is proposed. First, the hyperspectral image is partitioned into multiple subsets of adjacent hyperspectral bands. Then, the bands in each subset are fused together by averaging, which is one of the simplest image fusion methods. Finally, the fused bands are processed with transform domain recursive filtering to get the resulting features for classification. Experiments are performed on different hyperspectral images, with the support vector machines (SVMs) serving as the classifier. By using the proposed method, the accuracy of the SVM classifier can be improved significantly. Furthermore, compared with other hyperspectral classification methods, the proposed IFRF method shows outstanding performance in terms of classification accuracy and computational efficiency.
TL;DR: A positive learning curve in implant dentistry is demonstrated in higher survival rates and lower complication rates reported in more recent clinical studies, and it is important to identify these complications and their etiology to make implant treatment even more predictable in the future.
Abstract: Purpose: The objective of this systematic review was to assess and compare the survival and complication rates of implant-supported prostheses reported in studies published in the year 2000 and before, to those reported in studies published after the year 2000. Materials and Methods: Three electronic searches complemented by manual searching were conducted to identify 139 prospective and retrospective studies on implant-supported prostheses. The included studies were divided in two groups: a group of 31 older studies published in the year 2000 or before, and a group of 108 newer studies published after the year 2000. Survival and complication rates were calculated using Poisson regression models, and multivariable robust Poisson regression was used to formally compare the outcomes of older and newer studies. Results: The 5-year survival rate of implant-supported prostheses was significantly increased in newer studies compared with older studies. The overall survival rate increased from 93.5% to 97.1%. The survival rate for cemented prostheses increased from 95.2% to 97.9%; for screw-retained reconstruction, from 77.6% to 96.8%; for implant-supported single crowns, from 92.6% to 97.2%; and for implant-supported fixed dental prostheses (FDPs), from 93.5% to 96.4%. The incidence of esthetic complications decreased in more recent studies compared with older ones, but the incidence of biologic complications was similar. The results for technical complications were inconsistent. There was a significant reduction in abutment or screw loosening by implant-supported FDPs. On the other hand, the total number of technical complications and the incidence of fracture of the veneering material was significantly increased in the newer studies. To explain the increased rate of complications, minor complications are probably reported in more detail in the newer publications. Conclusions: The results of the present systematic review demonstrated a positive learning curve in implant dentistry, represented in higher survival rates and lower complication rates reported in more recent clinical studies. The incidence of esthetic, biologic, and technical complications, however, is still high. Hence, it is important to identify these complications and their etiology to make implant treatment even more predictable in the future.
TL;DR: The results indicate that adding CCS data to searchable databases and to routine metabolomics workflows will increase the identification confidence compared to traditional analytical approaches.
Abstract: Metabolomics is a rapidly evolving analytical approach in life and health sciences. The structural elucidation of the metabolites of interest remains a major analytical challenge in the metabolomics workflow. Here, we investigate the use of ion mobility as a tool to aid metabolite identification. Ion mobility allows for the measurement of the rotationally averaged collision cross-section (CCS), which gives information about the ionic shape of a molecule in the gas phase. We measured the CCSs of 125 common metabolites using traveling-wave ion mobility-mass spectrometry (TW-IM-MS). CCS measurements were highly reproducible on instruments located in three independent laboratories (RSD < 5% for 99%). We also determined the reproducibility of CCS measurements in various biological matrixes including urine, plasma, platelets, and red blood cells using ultra performance liquid chromatography (UPLC) coupled with TW-IM-MS. The mean RSD was < 2% for 97% of the CCS values, compared to 80% of retention times. Finally...
TL;DR: The so-called Otsu problem is solved for each channel of the multispectral and hyperspectral data and the problem of n-level thresholding is reduced to an optimization problem in order to search for the thresholds that maximize the between-class variance.
Abstract: Hyperspectral remote sensing images contain hundreds of data channels. Due to the high dimensionality of the hyperspectral data, it is difficult to design accurate and efficient image segmentation algorithms for such imagery. In this paper, a new multilevel thresholding method is introduced for the segmentation of hyperspectral and multispectral images. The new method is based on fractional-order Darwinian particle swarm optimization (FODPSO) which exploits the many swarms of test solutions that may exist at any time. In addition, the concept of fractional derivative is used to control the convergence rate of particles. In this paper, the so-called Otsu problem is solved for each channel of the multispectral and hyperspectral data. Therefore, the problem of n-level thresholding is reduced to an optimization problem in order to search for the thresholds that maximize the between-class variance. Experimental results are favorable for the FODPSO when compared to other bioinspired methods for multilevel segmentation of multispectral and hyperspectral images. The FODPSO presents a statistically significant improvement in terms of both CPU time and fitness value, i.e., the approach is able to find the optimal set of thresholds with a larger between-class variance in less computational time than the other approaches. In addition, a new classification approach based on support vector machine (SVM) and FODPSO is introduced in this paper. Results confirm that the new segmentation method is able to improve upon results obtained with the standard SVM in terms of classification accuracies.
TL;DR: Arguments for a genetic contribution to autism, based on updated family and twin studies, are examined and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed.
Abstract: Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene X environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention and early therapeutic intervention of ASD.
TL;DR: The method uses total variation to regularize an ill-posed problem dictated by a widely used explicit image formation model and produces images of excellent spatial and spectral quality.
Abstract: In this letter, we present a new method for the pansharpening of multispectral satellite imagery. Pansharpening is the process of synthesizing a high spatial resolution multispectral image from a low spatial resolution multispectral image and a high-resolution panchromatic (PAN) image. The method uses total variation to regularize an ill-posed problem dictated by a widely used explicit image formation model. This model is based on the assumptions that a linear combination of the bands of the pansharpened image gives the PAN image and that a decimation of the pansharpened image gives the original multispectral image. Experimental results are based on two real datasets and the quantitative quality of the pansharpened images is evaluated using a number of spatial and spectral metrics, some of which have been recently proposed and do not need a reference image. The proposed method compares favorably to other well-known methods for pansharpening and produces images of excellent spatial and spectral quality.
Houston Methodist Hospital1, RMIT University2, University of Iceland3, University of Turku4, Norwegian Institute of Public Health5, Mount Sinai Hospital, Toronto6, Public Health Agency of Sweden7, Karolinska University Hospital8, Karolinska Institutet9, National Center for Immunization and Respiratory Diseases10, Statens Serum Institut11
TL;DR: Analysis of 3,615 genome sequences permitted us to delineate the nature and timing of molecular events that contributed to an ongoing global human epidemic of infections caused by group A Streptococcus, the “flesh-eating” pathogen, and resolve a decades-long controversy about the type and sequence of genomic alterations that produced this explosive epidemic.
Abstract: We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion from a precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD+-glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population-based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide.
Erasmus University Rotterdam1, Massachusetts Institute of Technology2, University of Queensland3, Union College4, University of Iceland5, University of Minnesota6, VU University Amsterdam7, QIMR Berghofer Medical Research Institute8, Harvard University9, University of Illinois at Urbana–Champaign10, Leiden University Medical Center11, Drug Abuse Resistance Education12, University Medical Center Groningen13, University of Edinburgh14, Karolinska Institutet15, University of Bristol16, VU University Medical Center17, University of Dundee18, King's College London19, Stockholm School of Economics20, Cornell University21, New York University22, University of Amsterdam23
TL;DR: This article identified common genetic variants associated with cognitive performance using a two-stage approach, which they call the proxy-phenotype method, and measured the association of these education-associated SNPs with the cognitive performance.
Abstract: We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.
TL;DR: For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD‐based interventional thresholds for osteoporosis and at corresponding preestablished thresholds for “fragile bone strength”.
Abstract: Finite element analysis of computed tomography (CT) scans provides non-invasive estimates of bone strength at the spine and hip. To further validate such estimates clinically, we performed a five-year case-control study of 1110 women and men over age 65 from the AGES-Reykjavik cohort (case = incident spine or hip fracture; control = no incident spine or hip fracture, respectively). From the baseline CT scans, we measured femoral and vertebral strength, as well as bone mineral density (BMD) at the hip (areal BMD only) and lumbar spine (trabecular volumetric BMD only). We found that, for incident radiographically-confirmed spine fractures (n=167), the age-adjusted odds ratio for vertebral strength was significant for women (2.8, 95% CI: 1.8–4.3) and men (2.2, 95% CI: 1.5–3.2), and for men, remained significant (p=0.01) independent of vertebral trabecular volumetric BMD. For incident hip fractures (n=171), the age-adjusted odds ratio for femoral strength was significant for women (4.2, 95% CI: 2.6–6.9) and men (3.5, 95% CI: 2.3–5.3) and remained significant after adjusting for femoral neck areal BMD in women and for total hip areal BMD in both sexes; fracture classification improved for women by combining femoral strength with femoral neck areal BMD (p=0.002). For both sexes, the probabilities of spine and hip fractures were similarly high at the BMD-based interventional thresholds for osteoporosis and at corresponding pre-established thresholds for “fragile bone strength” (spine: women ≤ 4,500 N, men ≤ 6,500 N; hip: women ≤ 3,000 N, men ≤ 3,500 N). Since it is well established that individuals over age 65 who have osteoporosis at the hip or spine by BMD criteria should be considered at high risk of fracture, these results indicate that individuals who have “fragile bone strength” at the hip or spine should also be considered at high risk of fracture.
Centre for Life1, Council on Education for Public Health2, Karolinska Institutet3, University of Tartu4, Leiden University Medical Center5, deCODE genetics6, University of Calabria7, Delft University of Technology8, National Institute for Health Research9, Wellcome Trust Sanger Institute10, Queen's University Belfast11, University of Kiel12, Newcastle University13, Max Planck Society14, VU University Medical Center15, VU University Amsterdam16, University of Iceland17, Belfast Health and Social Care Trust18, Estonian Biocentre19, University of Southern Denmark20, University of Bristol21, Erasmus University Rotterdam22, University of Glasgow23, University of Paris24, University of Copenhagen25, Odense University Hospital26, University of Bologna27
TL;DR: The first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population is reported, with the minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure.
Abstract: The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.